Patients must undergo a careful diagnostic workup to stage their disease. Before developing active myeloma, patients pass through two earlier disease stages. These precursor stages are monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). 

MGUS

The earliest stage of myeloma is not cancer at all. Rather, this stage is a benign condition called monoclonal gammopathy of undetermined significance. Shortened as MGUS, it is pronounced "EM-guss."

  • MGUS patients have:
  1. a low level of a type of blood protein (monoclonal protein, also called M-protein) 
  2. a low level of abnormal plasma cells in the bone marrow,
  3. no indicators of active disease.

 

  • All patients with active myeloma once had MGUS.
  • Only 20% of patients with MGUS actually progress to active myeloma.
  • The risk of a patient's progression from MGUS to active myeloma is only 1% per year. 
  • A hematologist/oncologist should monitor patients with MGUS.
  • MGUS patients do not need to undergo treatment unless they choose to take part in a clinical trial.
     

SMM

Smoldering multiple myeloma (SMM) is

  • asymptomatic
  • an intermediate stage of myeloma between MGUS and active myeloma
  • Patients with SMM have a higher level of monoclonal protein and more abnormal plasma cells in the bone marrow than patients with MGUS.
  • These patients do not have any CRAB criteria, or damage to red blood cells, kidneys, or bones.
  • SMM can be thought of as a range of different stages of disease with three distinct possibilities:
  1. MGUS with a higher but stable number of abnormal plasma cells.
  2. Minimally progressive myeloma without CRAB criteria or myeloma-defining events.
  3. Moderately progressive myeloma, but with no damage to red blood cells, kidneys, or bones.

Your doctor should monitor your status regularly. Be sure to inform your doctor about any changes in your health status.

  • The risk of progression to active myeloma for patients with standard-risk SMM is:
  1. Ten-percent per year for the first five years
  2. Three-percent per year for the next five years
  3. One to two-percent per year for the next 10 years.

 

  • The standard of care for SMM is not to treat the patient but to "watch and wait." 
  • There are clinical trials are available to treat patients with SMM and "high-risk" SMM before their disease progresses.
  • Consult a hematologist/oncologist to tell apart MGUS, SMM, and active myeloma. 
  • If possible, consult with a myeloma specialist to avoid either unnecessary or delayed treatment.
     

Myeloma

  • Active myeloma may be diagnosed for either of the following reasons:
  1. Specific tests show a risk of progression to CRAB criteria within 18 months to 2 years. CRAB criteria include damage to bones, red blood cells, and/or kidneys.
  2. The patient already has one or more of the CRAB criteria.
     
  • Until 2014, patients were not diagnosed with myeloma unless they had one or more of the CRAB criteria.  In 2014, the IMF's International Myeloma Working Group (IMWG) published new diagnostic criteria based on biological markers. These markers could predict that one or more of the CRAB criteria would occur within 18 months to 2 years in patients with "ultra-high-risk myeloma."  
  • "Myeloma-defining events" (MDE) are another name for these biological markers.
  •  "Early active myeloma" is the new definition of "ultra-high risk myeloma." Healthcare professionals recommend treating "early active myeloma." 
     

Definitions of MGUS, SMM, and Myeloma

NAME DEFINITION
Monoclonal gammopathy of undetermined significance (MGUS) · Monoclonal protein present but usually ‹ 3.0 g/dL
· No CRAB features or other indicators of active myeloma
· Bone marrow monoclonal plasma cells ‹ 10%
Smoldering multiple myeloma (SMM) · Higher level of disease than MGUS: serum M-component can be › 3.0 g/dL and/or bone marrow plasma cells › 10%, but
· No CRAB features or other indicators of active myeloma
Myeloma based on MDE · ≥ 60% bone marrow plasma cells
· Free light chain ratio ≥ 100
· > 1 MRI focal lesion
Myeloma based on CRAB · Monoclonal protein present, and
· One or more CRAB features and/or indicators of organ damage

*Organ damage classified as "CRAB" or any other significant clinical problem linked to myeloma progression such as recurrent infections or neuropathy unrelated to treatment.

C - Calcium elevation (> 10mg/dL).

R - Renal dysfunction (creatinine > 2mg/dl or creatinine clearance (< 40ml/min).

A - Anemia (hemoglobin < 10g/dL or > 2g/dL decrease from patient's normal).

B - Bone disease (one or more osteolytic lesions detected on skeletal radiography, WBLC CT or PET/CT).

One or more "CRAB" features or other significant problem required for diagnosis of symptomatic myeloma.

 

New Definitions of Myeloma and Early Myeloma

Myeloma is a cancer of the plasma cells. Plasma cells are white blood cells that make antibodies. In medical terms, these antibodies are complex proteins called "immunoglobulins." They fight foreign substances such as bacteria and viruses.

Myeloma cells, unlike healthy plasma cells, cannot make functioning antibodies. Instead, they make an abnormal immunoglobulin known as "monoclonal protein." This results in a reduced ability to fight infection. Myeloma grows within the bone marrow. The presence of immunoglobulins may also cause other problems within the bone marrow and/or outside the bone marrow.
 

Multiple Myeloma Definitions and Staging

 

Medical Problems Related to Myeloma

Effects of Increased Myeloma Cells
in the Bone Marrow


CRAB criteria

 

Cause Impact on Patient
C - Increase in blood calcium Release of calcium from damaged bone into bloodstream.
  • Mental confusion
  • Dehydration
  • Constipation
  • Fatigue
  • Weakness
  • Renal or kidney damage
R -Renal problems in kidney damage Abnormal monoclonal proteins produced by the myeloma cells are released into the bloodstream and can pass into the urine and produce kidney damage. High blood calcium, infections, and other factors can also cause or increase the severity of kidney damage.
  • Sluggish circulation
  • Fatigue
  • Mental confusion
A - Anemia Decrease in the number and activity of red blood cell-producing cells in the bone marrow.
  • Fatigue
  • Weakness
B - Bone Damage
  • Thinning (osteoporosis) or
  • Areas of more severe damage (called lytic lesions), fracture, or collapse of a vertebra
The myeloma cells activate osteoclast cells, which destroy bone, and block osteoblast cells, which normally repair damaged bone.
  • Bone pain
  • Bone swelling
  • Fracture or collapse of a bone
  • Nerve or spinal cord damage
Additional types of organ dysfunction Local or systemic effects of myeloma, other than CRAB features.
  • Neuropathy
  • Recurrent infections
  • Bleeding problems
  • Other individual problems
Abnormal immune function The myeloma cells reduce the number and activity of normal plasma cells capable of producing antibodies against infection.
  • Susceptibility to infection
  • Delayed recovery from infection

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